Scientists race to be first to clone cash

Scientific breakthrough, ethical nightmare or just an overhyped bid for more money? ANDREW LAXON reports on animal transplants and the five little pig clones.

Scientists are claiming yet another breakthrough in the world of cloning.

Researchers at PPL Therapeutics, which helped create the world's first cloned animal, Dolly the sheep, announced last week that they had cloned five genetically engineered pigs with organs likely to be suitable for human transplants.

Millie, Christa, Alexis, Carrel and Dotcom (or, as they were originally christened, Noel, Angel, Star, Joy and Mary) were born on Christmas Day in PPL's American research division in Virginia.

Their birth means pigs have become the fourth mammal to be cloned, after cattle, mice and sheep.

More controversially, the piglets' modified genes have been designed to overcome rejection by the human immune system, increasing the chances that animal organs will some day be implanted in people.

To listen to the company last week, this was only a short step away.

Research director Alan Colman declared the promise of xenotransplantation (using animal organs for human transplants) had become a reality "with the potential to revolutionise the transplant industry".

Another spokesman called it "the only near-term solution to solving the worldwide organ shortage".

The safe use of animal organs for transplants would certainly solve a dilemma for doctors and patients everywhere, as compatible human organs are often not available.

In New Zealand alone, about 400 people are waiting for transplants. About 350 need kidneys, for which the average wait on dialysis is close to three years.

The wait for other organs is shorter but more perilous - about 40 per cent of patients with acute liver failure die because they cannot get a replacement within two days.

As a result, the search for alternatives offers huge financial rewards for a company which can beat the safety fears and technical hurdles.

Analysts predict the global market in solid organs is worth about $US5 billion ($11.8 billion), and $US6 billion for "soft" tissue transplants.

Since Dolly the sheep arrived in 1996, PPL and its rivals have been racing to develop a solution using cloning technology. The company's managing director in Scotland, Ron James, said the five little pigs project involved techniques subtly different from those used to make Dolly.

PPL scientists took a cell from an adult female pig and fused it with a pig egg whose own genes had been removed.

That newly formed cell began to divide like an embryo, even though it contained the genes not of two parents but of the single sow from which the initial cell had been taken.

Scientists made genetic changes in the initial cell before it started to grow into a pig embryo. That way every cell in the developing clone - including all the cells in the organs to be harvested later - would contain the crucial genetic changes aimed at avoiding rejection by humans.

One goal is to "knock out" a key pig gene called alpha 1-3 gal transferase, which directs pig cells to make a protein the human immune system quickly recognises as nonhuman.

Many scientists consider that gene to be the primary culprit in the radical rejection reaction that often occurs within minutes or hours of an unmatched transplant.

Scientists also want to add certain genes to the starter cell that will grow into a clone, including a gene that would inhibit any subsequent, delayed attacks by the human immune system, and a gene that would prevent blood clots from forming around the transplant.

PPL hopes to finish that work within three years, after which it plans to test the pig organs in monkeys or baboons. It hopes to conduct the first human transplants in four years.

Many scientists are impressed, but also sceptical.

"What they've done is terribly important. It's wonderful," said Fritz Bach, an immunologist at Harvard Medical School who serves as a consultant for Novartis Pharma AG, which owns PPL's leading competitor, Imutran, of Cambridge, England.

Dr Bach told the Washington Post that scientists could now move on to creating cloned pigs from which individual pig genes had been deleted, or human ones added, to learn how to make organs that would not be recognised as "foreign" by the human immune system.

But he and others dismissed the notion, touted in a PPL news release, that with the latest cloning success "all the known technical hurdles [to cross-species transplants] have been overcome".

"Organ rejection is a very complex series of problems, and I don't think any of us yet quite know what we're going to have to do to get over that," he said.

Imutran called the announcement "interesting news", but pointed out that the crucial next step was to see if organs from the genetically modified animals could be transplanted into humans without rejection.

Other competitors were less restrained, or even sarcastic.

"Well, I guess we may as well give them the Nobel Prize right now," said Jonathan Allan, a virologist at the Southwest Foundation for Biomedical Research in San Antonio, Texas, and a member of a US Food and Drug Administration advisory committee on xenotransplantation.

Fellow scientists have three main objections to what they regard as grandstanding by PPL.

First, they say it is unlikely that knocking out just one or even a few genes will be enough to make pig organs compatible with the human body.

Second, there is a risk that an Aids-like virus found in pigs could infect humans if genetically altered cells are placed in our bodies.

Fear of this retrovirus has made regulatory agencies around the world extremely cautious about using pig cells, organs or tissue in humans.

Third, there is suspicion about PPL's timing and motives.

The company dropped its bombshell days before a similar announcement was expected from one of its American rivals - whose own gene knockout piglets were apparently born three months earlier.

The news was first delivered not to other scientists or the media but to the London stock exchange. PPL's share price soared but slumped 15 per cent a few days later when investors learned of the rival piglets and that Dolly had arthritis.

"This is another one of these forward-looking statements from these companies to make their investors happy," said Alix Fano, director of the Campaign for Responsible Transplantation, a New York-based coalition of scientific and animal welfare organisations that favour alternatives to xenotransplantation, such as increasing donations from people.

That sentiment was echoed by others, who noted that by announcing its results before publishing them in a scientific journal, the company could boast without risking criticism of the work by experts.

There were similar complaints in November when US company Advanced Cell Technology claimed to have made the world's first human cloned embryo.

Closer inspection showed the "early-stage embryo" had only developed to six cells.

Critics said there was no guarantee it would have lived and accused ACT of timing the story - carefully packaged as a world exclusive in Scientific American magazine - to drum up some much-needed financial backing.

In this country, Professor Stephen Munn, director of the liver transplant unit at Auckland Hospital and a former researcher in animal transplant technology in the US, said PPL's announcement was a step towards success, but no more.

He added that successful implantations of pig cells and tissues into humans in New Zealand and Sweden had quietened scientific fears that the retrovirus could spread to humans.

The New Zealand research has been done by Professor Bob Elliott, who has fought for years for permission to transplant pig cells into diabetes patients as a natural source of insulin. Diabetics need insulin to control their blood sugar levels or risk eye, kidney and nerve damage.

The aim of Professor Elliott's project - also one of the immediate aims of PPL's research - is to free diabetics from the need for regular insulin injections.

However, unlike PPL, his company Diatranz does not genetically modify the insulin-producing pancreas cells from pigs. Instead it coats the cells with a protective semi-permeable membrane to avoid rejection by the immune system.

Professor Elliott argues that PPL's genetic modification not only weakens the effectiveness of pig cells by making them more like the human cells susceptible to the disease which causes diabetes.

He says it also increases the risk of the Aids-like retrovirus jumping from pigs to humans - unlike his own GM-free approach, which he says PPL has asked him for but which he is not giving away.

Professor Elliott told the Herald yesterday that 18 people from his trials were now living healthily with pig cells inside them, six of them for the past six years.

He predicted "quite outstanding results" in the next few months from a 20-month clinical trial of his method at the University of New Mexico.

However, the research will no longer be carried out in New Zealand because of Ministry of Health concerns (misplaced in the professor's view) that his pig cell transplantations could infect humans with the retrovirus.

Diatranz has applied twice, but Professor Elliott says he will not bother trying again because of New Zealand's reluctance "to take any risks whatsoever" with animal transplant research.

Soon he is unlikely to have the opportunity.

A temporary 18-month ban on cloning humans and transplanting any animal material into people is expected to be passed by the Government in March, giving MPs more time to consider a bill dealing with the wider issues.

Feature: Cloning humans

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Human Cloning Foundation

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